POEMS syndrome: definitions and long-term outcome
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
POEMS syndrome: definitions and long-term outcome
Angela Dispenzieri, Robert A. Kyle, Martha Q. Lacy, S. Vincent Rajkumar, Terry M. Therneau, Dirk R. Larson, Philip R. Greipp,
Thomas E. Witzig, Rita Basu, Guillermo A. Suarez, Rafael Fonseca, John A. Lust, and Morie A. Gertz
The POEMS syndrome (coined to refer to enopathy), endocrinopathy, edema (pe- oped over time. More than 50% of pa-
polyneuropathy, organomegaly, endocri- ripheral edema, ascites, or effusions), and tients had a response to radiation, and
nopathy, M protein, and skin changes) skin changes. The median age at presen- 22% to 50% had responses to prednisone
remains poorly understood. Ambiguity tation was 51 years; 63% were men. Me- and a combination of melphalan and pred-
exists over the features necessary to es- dian survival was 165 months. With the nisone, respectively. We conclude that
tablish the diagnosis, treatment efficacy, exception of fingernail clubbing (P ⴝ .03) the median survival of patients with
and prognosis. We identified 99 patients and extravascular volume overload POEMS syndrome is 165 months, inde-
with POEMS syndrome. Minimal criteria (P ⴝ .04), no presenting feature, includ- pendent of the number of syndrome fea-
were a sensorimotor peripheral neuropa- ing the number of presenting features, tures, bone lesions, or plasma cells at
thy and evidence of a monoclonal plasma- was predictive of survival. Response to diagnosis. Additional features of the syn-
proliferative disorder. To distinguish therapy (P < .001) was predictive of sur- drome often develop, but the complica-
POEMS from neuropathy associated with vival. Pulmonary hypertension, renal fail- tions of classic multiple myeloma rarely
monoclonal gammopathy of undeter- ure, thrombotic events, and congestive develop. (Blood. 2003;101:2496-2506)
mined significance, additional criteria heart failure were observed and appear to
were included: a bone lesion, Castleman be part of the syndrome. In 18 patients
disease, organomegaly (or lymphad- (18%), new disease manifestations devel- © 2003 by The American Society of Hematology
Introduction
Associations between plasma cell dyscrasia and peripheral and peripheral neuropathy, as compared with 29 patients without
neuropathy are well recognized.1 One third to one half of peripheral neuropathy, had a higher incidence of hyperpigmenta-
patients with osteosclerotic myeloma have neuropathy,2-4 and tion, edema, skin thickening, hepatomegaly, hypertrichosis, and
one half of patients with myeloma and peripheral neuropathy clubbing. In 1980, Bardwick et al19 coined the acronym POEMS to
have osteosclerotic lesions.5 These figures contrast distinctly represent a syndrome characterized by polyneuropathy, organo-
with the 1% to 8% incidence of neuropathy in patients with megaly, endocrinopathy, M protein, and skin changes. Not repre-
classic multiple myeloma.6,7 sented in the acronym are several important features, including
In 1956, the interaction of plasma cell dyscrasia and peripheral sclerotic bone lesions, Castleman disease, papilledema, pleural
neuropathy was shown to be more complex with Crow’s1 descrip- effusion, edema, ascites, and thrombocytosis.8,20-22
tion of 2 patients with osteosclerotic plasmacytomas with neuritis No single test establishes the diagnosis of POEMS syndrome.
and other “striking features,” which included clubbing, skin Seemingly disparate signs and symptoms must be linked to
pigmentation, dusky discoloration of the skin, white fingernails, establish the diagnosis. Although several series have been re-
mild lymphadenopathy, and ankle edema. Scheinker’s autopsy case ported,8,19,22 ambiguity exists about the number of features neces-
in 1938 was the first report of what we now call POEMS syndrome, sary for diagnosis, effective therapies, and prognosis. The intercon-
Crow-Fukase syndrome, PEP syndrome (plasma cell dyscrasia, nections between POEMS syndrome, osteosclerotic myeloma, and
endocrinopathy, and polyneuropathy), or Takatsuki syndrome.8,9 Castleman disease are still under investigation. Cytokines have
The patient was a 39-year-old man with a solitary plasmacytoma, been implicated in the pathogenesis of the disease.23-25 POEMS
sensorimotor polyneuropathy, and localized patches of thickened appears to be mediated by an imbalance of proinflammatory
and deeply pigmented skin on the chest.3,10 Subsequently, others cytokines. Interleukin-1 (IL-1), IL-6, and tumor necrosis fac-
reported patients with osteosclerotic myeloma and peripheral tor-␣ inconsistently have been reported to be increased in associa-
neuropathy with organomegaly, skin changes, endocrinopathy, tion with the syndrome.26-28 Preliminary data suggest that vascular
edema, hypertrichosis, gynecomastia, and ascites.2-4,9,11-18 In a 1977 endothelial growth factor is an excellent candidate as a pathogenic
review by Iwashita et al,3 30 patients with osteosclerotic myeloma factor in POEMS29,30; it induces a rapid and reversible increase in
From the Division of Hematology and Internal Medicine; Section of Presented in abstract form at the 41st annual meeting of the American Society
Biostatistics; Division of Endocrinology, Diabetes, Metabolism, Nutrition, and of Hematology, New Orleans, LA, December 3-7, 1999.
Internal Medicine; and Department of Neurology; Mayo Clinic, Rochester, MN.
Reprints: Angela Dispenzieri, Division of Hematology and Internal
Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail:
Submitted July 31, 2002; accepted November 8, 2002. Prepublished online as dispenzieri.angela@mayo.edu.
Blood First Edition Paper, November 27, 2002; DOI 10.1182/blood-
2002-07-2299. The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
Supported in part by grants CA62242 and CA91561 from the National Institutes
of Health. © 2003 by The American Society of Hematology
2496 BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7 POEMS SYNDROME: A RETROSPECTIVE REVIEW 2497
vascular permeability, is a growth factor for endothelial cells, and is were classified as having had a good response. Patients whose deterioration
considered important in angiogenesis.27 stabilized during or after treatment but did not derive any subjective or
In a retrospective review of a single institution’s experience, we objective improvement were classified as having stable disease. Patients
defined the minimal criteria required for the diagnosis of POEMS who continued to deteriorate despite therapy were deemed refractory.
Curves for overall survival and time to the development of new
syndrome, described the natural history of the disease, and studied
syndrome features were plotted according to the method of Kaplan and
whether pulmonary hypertension, restrictive lung disease, thrombo- Meier31 and were compared by the log-rank test.32 Survival was calculated
sis, cardiomyopathy, and glomerulonephritis are true associations. from the time of diagnosis. Prognostic factors for overall survival and risk
of developing additional features were determined by the Cox proportional
hazards model in the analysis of covariates.33 Variables analyzed in these
Patients and methods models include the following: age, sex, organomegaly, papilledema, skin
abnormalities, endocrine abnormalities, edema, weight loss, lymphadenopa-
The Mayo Clinic dysproteinemia database was queried for all patients with thy, Castleman disease, number of POEMS features, thrombocytosis,
POEMS syndrome or osteosclerotic myeloma. One reviewer (A.D.) hemoglobin level, type of immunoglobulin heavy chain, bone marrow
abstracted data. Through December 1998, 99 patients were identified who plasmacytosis, serum M-protein level, urine M-protein level, number of
met the minimal criteria for study inclusion. The diagnosis had been made bone lesions, and type of treatment.
at our institution in 80 patients and elsewhere in 19 patients. All 99 patients
had both major criteria and one minor criterion for the diagnosis of POEMS
syndrome (Table 1).
All patients (or their physicians) for whom no follow-up data were Results
available in the preceding year were contacted. Death certificates were
sought for deceased patients for whom there was inadequate information. Presenting features
Follow-up data were available for 93 patients (94%). Median follow-up was
70.6 months (range, 0.2 to 304 months). Twenty-four patients (24%) were Patient characteristics are shown in Tables 2 and 3. Thirty-one
evaluated from 1960 to 1985, 33 (33%) from 1986 to 1990, and 42 (42%) patients (31%) were 45 years or younger; 62 (63%) were men.
from 1991 to 1998. The Mayo Foundation Institutional Review Board Table 3 compares the findings in this study with those of the 2 other
approved the study in accordance with Minnesota state law. largest patient series.8,22 The most notable differences among the
The definitions of response to treatment were based on both patient and studies are the high frequency of accompanying bone lesions in the
physician reports of improvement rather than on strictly defined objective present study (97% compared with 54% to 68%) and the lower
criteria. Patients who had little or no residual neuropathy and otherwise frequency in the present study of edema and effusions (29%
regained a normal sense of well-being and function were classified as
compared with 66% to 89%) and organomegaly (50% compared
having had a very good response. Those who had improvement in their
with 68% to 78%). In contrast to the other studies in Table 3, the
neuropathy but still perceived themselves to have a significant handicap
present series cites only the features present at diagnosis rather than
features observed during disease evolution and progression.
Table 1. Criteria for the diagnosis of POEMS syndrome*
Polyneuropathy
Major criteria Polyneuropathy
Monoclonal plasmaproliferative disorder Peripheral neuropathy is the dominant clinical feature of this disorder
Minor criteria Sclerotic bone lesions† (Table 3). By definition, all patients in this series had a peripheral
Castleman disease† neuropathy. Although neuropathy is typically the presenting symptom,
Organomegaly (splenomegaly, hepatomegaly, or in the present series 5 patients (5%) had a known plasma cell dyscrasia
lymphadenopathy) before the onset of the neuropathy.8,22 All patients in this series had
Edema (edema, pleural effusion, or ascites) increased cerebrospinal fluid protein, increased cerebrospinal fluid
Endocrinopathy (adrenal, thyroid,‡ pituitary, gonadal, opening pressures, and a normal cell count.8,22 Thirty-one patients (31%)
parathyroid, pancreatic‡)
had sural nerve biopsy; in most cases, the findings were those of a
Skin changes (hyperpigmentation, hypertrichosis,
demyelinating process with axonal loss.
plethora, hemangiomata, white nails)
Papilledema Organomegaly
Known associations Clubbing
Fifty patients (50%) had organomegaly. Twenty-six patients (26%)
Weight loss
Thrombocytosis
had lymphadenopathy. Of these 26, 15 underwent biopsy: 11 had
Polycythemia Castleman disease, and 4 had reactive changes. Twenty-four
Hyperhidrosis patients (24%) had hepatomegaly, and 22 (22%) had splenomegaly.
No patient had massive lymphadenopathy or organomegaly. The
Possible associations Pulmonary hypertension
percentage of patients with organomegaly in our series seems lower
Restrictive lung disease
Thrombotic diatheses
than that in other series (Table 3).
Arthralgias Endocrinopathy
Cardiomyopathy (systolic dysfunction)
Fever Endocrine abnormality is a defining feature of POEMS.19 In the
Low vitamin B12 values present study, 66 patients (67%) had at least one endocrine
Diarrhea
abnormality at presentation. Later in the course of disease,
POEMS indicates polyneuropathy, organomegaly, endocrinopathy, M protein, endocrine abnormalities developed in 7 other patients (7%). Most
skin changes. patients did not have a thorough endocrine evaluation, lowering the
*Two major criteria and at least 1 minor criterion are required for diagnosis.
reported incidence. Because both diabetes mellitus and hypothyroid-
†Osteosclerotic lesion or Castleman disease is usually present.
‡Because of the high prevalence of diabetes mellitus and thyroid abnormalities, ism are common endocrine abnormalities, care was taken to assign
this diagnosis alone is not sufficient to meet this minor criterion. them as part of the syndrome only if there appeared to be a clear2498 DISPENZIERI et al BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7
Table 2. Presenting clinical characteristics of 99 patients with POEMS hypothyroidism was the only endocrine abnormality. The remain-
syndrome
der had gonadal or adrenal dysfunction or both. In 6 other patients,
Characteristic %
hypothyroidism developed during the course of disease; they were
Median age, y (range) 51 (30-83) not included among those considered to have an endocrine
Race
abnormality at presentation (Table 3).
African American 8
Asian 0
Hispanic 3
Table 3. Comparison of clinical characteristics of patients in the present
Non-Hispanic white 89 series and 2 previous series*
Male sex 63
Present Soubrier Nakanishi
Patients with given no. of classic POEMS features*
study, % et al,22 % et al,8 %
2 features 7 Characteristic N ⫽ 99 N ⫽ 25 N ⫽ 102
3 features 32
Polyneuropathy
4 features 31
Peripheral neuropathy 100 100 100
5 features 29
Cerebrospinal fluid protein more
Patients with given no. of revised POEMS features†
than 50 mg/dL 100‡ 100‡ 97‡
3 features 6
Organomegaly 50 NR NR
4 features 19
Hepatomegaly 24 68 78
5 features 32
Splenomegaly 22 52 35
6 features 17
Lymphadenopathy 26 52 61
7 features 16
Castleman disease 11 24 19
8 features 7
Endocrinopathy 67 NR NR
9 features 2
Gonadal axis abnormality 55 NR NR
Laboratory value
Adrenal axis abnormality 16 NR NR
Albumin less than 3.0 g/dL (range) 24 (2.3-4.5)
Increased prolactin value 5 NR NR
Bone marrow plasma cells more than 10% (range) 14 (0-40)
Gynecomastia or galactorrhea 18 NR NR
Calcium more than 10.5 mg/dL (range) 0 (7.8-10.2)
Diabetes mellitus 3 36 25
Creatinine more than 1.5 mg/dL (range) 2 (0.5-1.9)
Hypothyroidism 14 36 NR
Erythrocyte sedimentation rate more than 29 mm/h (range) 16 (1-58)
Hyperparathyroidism 3 NR NR
Hemoglobin less than 11 g/dL (range) 4 (10.4-18.4)
Monoclonal plasma cell dyscrasia 100 100 75
Hemoglobin more than 16 g/dL (range) 16 (10.4-18.4)
M component on serum protein
Leukocytes more than 10 500/L (range) 21 (3700-17 600)
electrophoresis 54 100 70
Platelets more than 450 ⫻ 103/L (range) 54 (111-1163)
Skin changes 68 NR NR
Serum M-spike more than 2.0 g/dL (range) 7 (0.00-4.1)
Hyperpigmentation 46 48 93
Urine M-spike more than 0.5 g/24 h (range) 0 (0.00-0.45)
Acrocyanosis and plethora 19 NR NR
Urine protein more than 1.0 g/24 h (range) 5 (0.02-3.2)
Hemangioma/telangiectasia 9 32 NR
POEMS encompasses polyneuropathy, organomegaly, endocrinopathy, M pro- Hypertrichosis 26 24 74
tein, skin changes. Thickening 5 28 61
*According to Bardwick et al.19 Papilledema 29 40 55
†According to Table 1.
Extravascular volume overload 29 NR NR
Peripheral edema 24 80 89
Ascites 7 32 52
temporal relationship. The overall prevalence of endocrinopathy
Pleural effusion 3 24 35
was similar to that previously reported by others (Table 3).22,34
Bone lesions 97 68 54
Hypogonadism was most common, though laboratory data were Osteosclerotic only† 47 41 56
too sparse to determine whether there was primary or secondary Mixed sclerotic and lytic† 51 59 31
failure. Forty-four men (71%) had erectile dysfunction. Twenty- Lytic only† 2 0 13
eight of these men had serum testosterone levels measured; all but Solitary lesion† 45 41 45
4 had low levels. Of those not reporting sexual dysfunction, 5 had 2 or 3 lesions† 23 NR NR
low serum testosterone levels. Of the 19 men who had serum More than 1 lesion† 54 59 45
prolactin levels measured, none had high levels. Seventeen men More than 3 lesions† 32 NR NR
had gynecomastia; none of the 4 men tested had high serum Other features
Weight loss more than 10
estradiol levels. The sexual history of women was less reliably
pounds 37 NR NR
ascertained. Two women had irregular menses, one of whom also
Fatigue 31 NR NR
had galactorrhea. Serum estradiol levels were normal in all 4 Thrombocytosis: platelet count
women tested. Among the 25 patients with measured serum more than 450 ⫻ 103/L 54 88 NR
prolactin levels, levels were high (range, 26 to 58 g/mL [26 to 58 Polycythemia: hemoglobin more
ng/L]; normal, less than 23 g/mL [23 ng/L]) in 3 men and than 15 g/dL in women and
2 women. more than 17 g/dL in men 18 12 19
Fourteen patients (14%) had hypothyroidism requiring treat- Clubbing 5 32 49
ment. Another 12 patients (12%) had mild increases in thyroid- NR indicates not reported.
stimulating hormone (5.8 to 13.4 mU/L [5.8 to 13.4 U/mL]; *The percentage of patients with the given characteristic is shown. Percentages
normal, 0.3 to 5.0 mU/L [0.3 to 5.0 U/mL]) and normal thyroxine are based on the total number of patients in the series, with the exception of
cerebrospinal fluid protein, which includes the actual number tested.
levels; these patients were not treated and therefore not considered
†Percentage of patients with bone lesions.
to have an endocrine abnormality in this series. The hypothyroid- ‡Only 28, 23, and 73 patients, respectively, were tested; percentage represents
ism was primary in 9 patients and secondary in 3. In 3 patients, percent positive of those tested.BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7 POEMS SYNDROME: A RETROSPECTIVE REVIEW 2499
Three patients (3%) had diabetes mellitus, having high fasting patients with POEMS syndrome, no mention of this finding was
glucose and glycosylated hemoglobin levels. Of the 35 patients made regarding the patients we studied.
who had adrenal-pituitary testing, 16 (16%) had abnormalities of
Edema and effusions
the adrenal-pituitary axis at presentation. In another 5 patients,
adrenal insufficiency developed later in the course of disease. In On presentation, 29 patients (29%) had some form of extravascular
total, 9 patients had primary adrenal dysfunction, 3 had secondary volume overload. Peripheral edema, ascites, and pleural effusions
adrenal dysfunction, and 10 had insufficient data to make were present in 24, 7, and 3 patients, respectively (Table 3). One
the distinction. patient had a pericardial effusion. The incidence of edema and
Serum levels of parathyroid hormone were measured in 4 effusions was lower in our series than in other series; however, if
patients and were found to be increased in 3. In one patient one includes patients in whom edema or effusions developed
hypoparathyroidism was diagnosed 84 months after POEMS during the course of disease, the numbers increase to 29, 15, and
syndrome was diagnosed. 9, respectively.
Monoclonal plasmaproliferative disorder Sclerotic bone lesions
By definition, all patients had evidence of a monoclonal plasmapro- On presentation, 95 patients had at least one abnormality
liferative disorder. Eighty-four patients (85%) had a detectable detected on radiographic bone survey (Table 3). Of the 4
monoclonal protein in their serum on analysis by immunofixation. patients not presenting with a bone lesion, all had 4 or 5 features
These findings are similar to those of Nakanishi et al,8 who found of POEMS syndrome, including a clonal plasmaproliferative
an M component to be present in 75% of patients. The serum disorder. In one patient, a sclerotic bone lesion developed 18
protein electrophoresis patterns of 24 of our patients were normal; months later, yielding a total of 96 patients (97%) with abnormal
patterns of 7 patients appeared polyclonal. Had immunofixation not findings on bone radiography. Of the patients with abnormal
been done, the monoclonal protein would have been missed in findings, all but 2 had sclerotic bone lesions. The radiographs
these 31 patients. Although 40 patients had a detectable monoclo- for these 2 patients could not be located to establish whether
nal protein in their urine, in only 3 patients did urine screening there was any element of sclerosis associated with the lytic
identify a monoclonal plasmaproliferative disorder that had not lesions. These 2 patients had solitary lytic lesions. In our
been detected in the serum. The quantity of monoclonal protein was experience, lytic lesions in patients with POEMS syndrome tend
small in both serum and urine, with a median serum M-spike of 11 to have a sclerotic rim. Forty-nine patients had lesions with
g/L (1.1 g/dL) (range, 0.0 to 41 g/L [4.1 g/dL]; only 7 patients had mixed sclerotic and lytic components. Forty-three patients had a
an M-spike more than 20 g/L [2 g/dL]) (Table 2). The median total solitary lesion, 22 had 2 or 3 lesions, and 31 had more than 3
urine protein was 100 mg per 24 hours. lesions (Table 3). These findings are consistent with those of
All patients had a monoclonal light chain. Forty-four patients previous publications.8,22 Twenty-two patients underwent bi-
had an immunoglobulin A (IgA) , 40 had an IgG , and 1 had an opsy of a sclerotic lesion; results were diagnostic in 20.
IgM . For the 12 patients who did not have a monoclonal protein
Papilledema
in their serum or urine, a clonal plasmaproliferative disorder was
demonstrated by immunohistochemical staining of biopsy speci- Papilledema was observed in 29 patients (29%) (Table 3). In other
mens from sclerotic bone lesions or bone marrow. series, papilledema has been observed in 40% to 55% of patients.8,22
Of 90 patients who had a bone marrow biopsy performed, the
Other established features
most common interpretation was “nondiagnostic,” with the predomi-
nant feature being a hypercellular or “reactive-appearing” marrow. Thirty-seven patients (37%) had lost more than 10 pounds of body
Twenty-one patients had a normal-appearing marrow. Only 4 weight at presentation. Thirty-one patients (31%) complained of
patients had more than 20% plasma cells; none of these 4 patients significant fatigue. Five patients (5%) had recognized clubbing at
had lytic bone disease or anemia. In 25 patients, there was only a diagnosis, one of whom had coincident restrictive lung disease.
slight increase in plasma cells (Tables 2 and 3). Our finding that Patients with clubbing seemed to have more extensive disease: all
14% of patients had a bone marrow plasmacytosis more than 10% had organomegaly, endocrinopathy, skin changes, peripheral neu-
is similar to the 5% to 20% previously reported.8,22 ropathy, and plasmaproliferative disorder; in all but one of these
Skin changes
patients, additional POEMS features developed over time. Thirteen
patients (13%) complained of generalized bone pain or arthralgia;
Skin changes were documented in 67 patients (68%) (Table 3). only 3 of these patients had diffuse sclerotic lesions. Fifty-three
The most common abnormality was hyperpigmentation (46 patients (54%) had thrombocytosis, and 18 (18%) had polycythe-
patients), followed by acrocyanosis and plethora (19 patients). mia (hemoglobin more than 150 g/L [15 g/dL] in women and more
The latter 2 features were not well-captured in the other large than 170 g/L [17 g/dL] in men).
series, but they are described elsewhere.1,8,22,35 Five patients had
Unusual features
skin thickening. Multiple hemangiomas were documented in 9
patients; vascular changes similar to those in Kaposi sarcoma Data from case reports and small series suggest that pulmonary
were seen in one of these patients. A necrotizing vasculitis along hypertension, congestive heart failure, thrombosis, and renal
with hyperpigmentation was present in another patient. Of the failure may be part of the POEMS syndrome (Table 1).7,29,36-76 In
26 patients with hypertrichosis, only 5 had no endocrine the present series, 47 patients had one or more of these features.
abnormality, and only 4 had no other skin abnormalities. The Fourteen patients had lung disease other than effusion during
hypertrichosis was either generalized or limited to body parts, the course of their illness; 3 had effusion, one of whom also had
such as the extremities or face. Twenty-nine patients had 2 or 3 other pulmonary manifestations. Five patients had pulmonary
coexistent skin abnormalities. Although white nails can occur in hypertension. Five patients had restrictive lung disease. In 42500 DISPENZIERI et al BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7
patients, respiratory failure or insufficiency developed within
several months before death; 17% of deaths were due to
respiratory failure.
Four patients died of complications of renal failure between 34
and 120 months after diagnosis. The renal failure occurred within 6
months before death in 3 patients and 3 years before death in 1.
There was associated ascites in 3 of the 4 patients. No renal
biopsies were performed. All patients who died of renal failure had
coexistent ascites and a capillary leaklike syndrome.
Congestive heart failure and cardiomyopathy were among the
presenting features in 3 patients. After treatment of the plasma cell Figure 2. Survival on the basis of treatment with radiation. P ⬍ .04 for
dyscrasia with either radiation or combination chemotherapy, comparison of the 2 groups.
cardiac symptoms resolved in all 3 patients. In 4 other patients,
congestive heart failure developed at 12, 30, 56, and 192 months. Long-term follow-up of patients with POEMS syndrome
Each of the cardiac events occurred during a POEMS exacerbation. Not only are the number of features present at diagnosis not
Two patients had pericarditis within a few months of presentation. prognostic of survival (Figure 3), but patients often accumulate
Twenty-one thrombotic events (10 venous, 11 arterial) occurred additional features of POEMS syndrome over time (Table 5). In our
in 18 patients. Seven patients had 8 thrombotic events predating cohort, the median time between onset of symptoms and diagnosis
their diagnosis with POEMS. Eleven patients had 13 events was 15 months (range, 3-120 months). The respective median times
after diagnosis. in months from the initial occurrence of symptoms to diagnosis for
patients with 2, 3, 4, and 5 features at presentation were 11 (range,
Survival and prognostic features
5-60); 13 (range, 3-60); 15 (range, 3-48); and 21 (range, 3-120).
Overall median survival was 165 months (Figure 1). Only finger- Moreover, during follow-up additional classic POEMS characteris-
nail clubbing and extravascular volume overload (edema, effusion, tics developed in 18 patients; possible POEMS features (congestive
or ascites) were prognostic for survival. Patients with clubbing or heart failure and thrombosis) developed in 7 other patients.
extravascular volume overload had a median survival of 31 and 79 Seven patients had only 2 of the 5 POEMS features as described
months, respectively. These variables were independent of each by Bardwick et al,19 namely, the monoclonal plasmaproliferative
disorder and peripheral neuropathy. All 7 patients had at least 1
other, and their corresponding proportional hazard ratios for death
osteosclerotic bone lesion; in fact, 6 had more than 1 lesion.
were 4.0 (P ⫽ .03) and 2.1 (P ⫽ .04). Patients who received
Additional POEMS features subsequently developed in 2 (Table 5).
radiation therapy and those who had a very good or good response
Among the 32 patients with 3 features of POEMS, additional
to treatment also had superior survival (Figure 2).
features developed in 5 patients 9 to 60 months after the original
When we used the criteria of Bardwick et al,19 median survival diagnosis. Among the 31 patients with 4 features of POEMS, other
for patients with 2, 3, 4, and 5 features at presentation was more features subsequently developed in 6. Finally, among the 29
than 174, 85, more than 302, and 96 months, respectively; 29%, patients with all 5 features, other POEMS features developed in 4.
50%, 23%, and 34% of the patients in the respective groups have Presenting features were evaluated for their value in predicting
died. When we used the 9 major and minor criteria in Table 1, the development of other POEMS features. On univariate analysis,
median survival for patients with 3, 4, 5, 6, 7, 8, and 9 features was the only factors predictive of the development of additional
more than 174, 85, more than 302, 49, more than 197, 103, and 50 POEMS features were a serum M-spike of more than 1 g/dL
months, respectively (P ⫽ not significant) (Figure 3); 17%, 47%, (P ⫽ .04), the presence of a monoclonal protein in the urine
25%, 53%, 25%, 29%, and 100% of the patients in the respective (P ⫽ .05), and the absence of radiation therapy (P ⫽ .02). On
groups have died. In toto, 35 patients have died (Table 4). The most multivariate analysis, only the presence of a urinary monoclonal
commonly identified causes of death were cardiorespiratory failure protein was predictive of the development of additional features
and infection. No patient died of classic myeloma—that is, (proportional hazards, 4.82; confidence interval, 1.71-13.8;
progressive bone marrow failure or hypercalcemia. All patients P ⫽ .003). Among the 18 patients in whom additional POEMS-
who died of renal failure had coexistent ascites and a capillary associated features developed over time, those patients with the
leaklike syndrome.
Figure 1. Overall survival for 99 patients with POEMS syndrome evaluated at a Figure 3. Survival on the basis of number of features at presentation. P ⫽ not
single institution. significant. MS indicates median survival; Pts, patients.BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7 POEMS SYNDROME: A RETROSPECTIVE REVIEW 2501
Table 4. Causes of death among 35 patients with alkylator-based combination chemotherapy, 41 with pred-
Cause of death No. of patients* nisone or dexamethasone alone, 30 with plasmapheresis, and 9
Cardiac event 7†‡ with intravenous immunoglobulin.
Respiratory failure 6‡ A response was defined as stabilization or improvement of
Infection 4 symptoms as reported by the patient or the treating physician.
POEMS 3 Radiation therapy was effective; at least half of patients so treated
Cancer 3§ responded. Only those patients with a solitary lesion or a dominant
Renal failure 4㛳 lesion were treated with radiation. Of the 13 patients who did not
Unknown 5
respond to radiation, 9 had received less than 4000 cGy. Responses
Other 5#
were often inapparent until 3 to 6 months after treatment. Some
*The deaths of 2 patients were attributed to more than 1 cause. patients showed continued improvement 1 to 2 years after radiation
†Includes 3 patients with congestive heart failure. treatment. Responses of organomegaly and skin changes generally
‡Includes 1 patient who died of cardiorespiratory arrest.
§Includes acute myelogenous leukemia, cholangiocarcinoma, and cancer not
antedated a response of neuropathy.
otherwise specified. Clinical responses to prednisone and a combination of melpha-
㛳Includes 1 patient who died of shock and renal failure. lan and prednisone occurred in approximately 22% to 56% of
#Includes suicide, cachexia, inanition, shock, and stroke.
patients. Patients receiving plasmapheresis, cyclosporine, or azathio-
prine responded only if they were also receiving prednisone,
fewest POEMS features as described by Bardwick et al19 had the suggesting that these agents themselves are ineffective. No re-
highest risk of additional features developing (29% vs 14%). sponse was observed with intravenous immunoglobulin.
Therapy
Patients were either treated by Mayo Clinic physicians or referred Discussion
for treatment to their local physicians. Because this was a Clinical features
retrospective analysis, it was difficult to draw firm conclusions
regarding therapy. However, we found that 73 patients (74%) had at All patients with POEMS syndrome have peripheral neuropathy
least some response to therapy (Table 6). Fourteen patients were and a monoclonal plasma cell dyscrasia or Castleman disease.
refractory to the treatments chosen. Sixty-four patients were treated Hepatomegaly, splenomegaly, lymphadenopathy, endocrinopathy,
with 70 courses of radiation, 48 with melphalan and prednisone, 15 skin changes, papilledema, peripheral edema, ascites, sclerotic
Table 5. Acquisition of POEMS syndrome features over time
Patient
characteristics Initial POEMS features
Response Current
No. Sex Age, y P O E M S A B, no. C Pap Subsequently acquired POEMS features TTP, y FU, y to therapy status
1 F 66 P M Diff Hypothyroid, hypoadrenal at 126 mo; ascites, 10.5 14.5 V gd Alive
pulmonary hypertension at 156 mo
2 F 34 P M 2 or 3 Ascites, Budd-Chiari at 149 mo; pleural effusion 12.4 13.4 V gd Alive
at 156 mo
3 F 34 P M S Diff Detectable monoclonal protein in serum at 39 mo; 5.0 7.8 Stable Dead
hypothyroid at 60 mo; ascites and
hepatomegaly at 87 mo
4 M 46 P O M A Diff Pulmonary hypertension and effusion at 36 mo; 3.0 5.8 Good Alive
hypothyroid at 52 mo; acrocyanosis at 54 mo
5 F 58 P M S A Diff Pap Hypothyroid at 9 mo; ascites and renal failure 0.8 3.3 Good Dead
at 12 mo
6 M 43 P M S 2 or 3 Hypoadrenal at 4 mo 0.3 1.0 Refr Alive
7 F 50 P M S 1 Pericardial effusion at 1 mo 0.1 0.2 Refr Dead
8 M 38 P E M S 1 CHF, hypogonad, hypothyroid, hypoadrenal, 16.0 16.4 V gd Alive
peripheral edema, acrocyanosis,
hypertrichosis, hyperpigmentation at 192 mo
9 F 33 P E M S 1 Pap Peripheral edema at 90 mo 7.5 9.5 V gd Alive
10 M 56 P E M S 2 or 3 Diabetes mellitus at 94 mo 7.8 9.1 V gd Alive
11 F 44 P E M S 1 Pap Ascites and CHF at 56 mo 4.7 5.0 Good Dead
12 M 51 P O M S Diff C Clubbing, ascites, and renal failure at 52 mo 4.3 4.9 ND Dead
13 F 61 P E M S 2 or 3 Ascites at 1 mo 0.1 0.7 ND Alive
14 F 57 P O E M S A Diff Ascites at 22 mo; renal failure and oxygen 1.8 10.0 V gd Dead
dependence at 117 mo
15 F 50 P O E M S 2 or 3 Pap Ascites at 12 mo; respiratory failure at 66 mo 1.0 5.7 Good Dead
16 M 51 P O E M S 2 or 3 Hepatomegaly and hepatic dysfunction at 30 mo 2.5 2.8 Good Dead
17 M 39 P O E M S 1 Lymphadenopathy at 17 mo; restrictive lung 1.4 1.4 Good Alive
disease at 36 mo
18 M 64 P O E M S A Diff Pap Hypoparathyroid at 84 mo 7.0 14.6 Good Alive
A indicates anasarca, edema, ascites, or pleural effusion; B, bone lesions; C, Castleman disease; CHF, congestive heart failure; Diff, diffuse; E, endocrinopathy;
FU, follow-up; M, monoclonal plasma cell dyscrasia; ND, no data; O, organomegaly (including hepatomegaly, splenomegaly, and lymphadenopathy); P, peripheral neuropathy;
Pap, papilledema; Refr, refractory disease; S, skin changes; TTP, time to progression; and V gd, very good.2502 DISPENZIERI et al BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7
Table 6. Response to therapy in patients with POEMS syndrome
Response to treatment, %
Treatment No. of patients Improved Stable Progression Unknown
Radiation 70† 54 4 16 26
Melphalan and prednisone 48 44 12 12 31
Combination chemotherapy* 15 27 7 33 33
Cyclosporine or azathioprine 4 0 0 100 0
Cyclosporine or azathioprine, plus prednisone 6 50 0 17 33
Prednisone or dexamethasone 41 15 7 20 59
Plasmapheresis 16 0 12 87 0
Plasmapheresis plus prednisone 14 21 0 14 64
Intravenous immunoglobulin 9 0 0 89 11
*Includes vincristine, carmustine, melphalan, cyclophosphamide, and prednisone; vincristine, doxorubicin, and dexamethasone; cyclophosphamide, doxorubicin,
vincristine, and prednisone; and cyclophospharnide-based chemotherapy.
†Sixty-four patients were treated with 70 courses of radiation.
bone lesions, clubbing, polycythemia, thrombocytosis, and fatigue responded.7,17,35,48,118,122-125 In our series, this occurred in 18% to
are all features of the syndrome.8,22 25% of patients, depending on whether one considers congestive
The neuropathy is symmetrical and ascending, with either an heart failure and thrombotic abnormalities to be part of the
insidious or rapidly progressing onset. Patients often describe syndrome. New features can develop more than 10 years after the
numbness and dysesthesias followed by a progressive ascending initial presentation.35 We therefore propose the concept that 2 major
weakness that overshadows the sensory impairment. In most criteria and at least 1 minor criterion should be met to establish the
patients, it is the presenting symptom; however, in one series diagnosis of POEMS syndrome.
edema preceded neuropathy in 12% of patients and coincided with
it in 14%.8 In our series, 5 patients had a known antecedent Survival
plasmaproliferative disorder. The neuropathy is seldom painful, The prognosis for patients with POEMS has been reported to be
and autonomic involvement is rare.5 It is typically a chronic, poor, with median survivals estimated to be 12 to 33 months.2,8,9
large-fiber sensorimotor neuropathy. Most authors have not found
However, this has not been our experience. In the present series,
monoclonal immunoglobulin associated with nerve speci-
median survival was 165 months. Reports of patients who have had
mens,8,36,37,77 except for Adams and Said78 and Broussolle et al.79
the disease for more than 5 years are not unusual.7,17,35,118,123,125 In
The estimate that 11% to 30% of POEMS patients have
one study, 7 of 15 patients were alive for more than 5 years, with 1
Castleman disease is conservative because many patients do not
patient living for 25 years.126
undergo lymph node biopsy.8,22 The association between the 2
Our data and those of others demonstrate that survival is not
disorders is well recognized but poorly understood.8,22,38,47,65,80-114
affected by the number of POEMS features,22 although clubbing
Endocrine abnormalities are defining features of the syndrome.19
and extravascular volume overload are associated with shorter
Primary and secondary hypothyroidism, hypogonadism, adrenocortical
survival. In the present series, 35 patients have died. Even patients
insufficiency, and diabetes mellitus have been described.19,22,86,97,115,116
with multiple bone lesions or those with more than 10% plasma
Parathyroid hormone abnormalities were found in 4 of our patients and
have been reported previously.2,100,117,118 cells do not progress to overt multiple myeloma. Bone fractures
Papilledema, which occurs in 29% to 55% of patients, may be rarely develop. The neuropathy may be unrelenting and contribute
asymptomatic or may cause headache, transient obscurations of to progressive inanition and eventual cardiorespiratory failure and
vision, scotomata, enlarged blind spots, or progressive constriction pneumonia. Stroke and myocardial infarction, which may or may
of the visual field.8,22,38,119 not be related to the POEMS syndrome, also are observed causes
Sclerotic bone lesions occur in most patients. They may be of death.
solitary or multiple. In the series of Soubrier et al,22 prognosis was Less-recognized features
significantly better for patients with solitary bone lesions. In our
series, survival was independent of the number of bone lesions. Less-recognized phenomena may be pulmonary hypertension,
However, response to therapy was better in patients with radiated restrictive lung disease, cardiomyopathy, and an increased inci-
dominant bone lesions. dence of arterial and venous thrombosis.
Clubbing may occur in up to 13% of patients.1,120 It is unclear At least 13 cases of pulmonary hypertension in patients with
whether the clubbing observed in patients with POEMS syndrome POEMS syndrome have been reported in previous series.36-45 In the
is a function of undiagnosed pulmonary hypertension121; regard- present series, we report an additional 5. Moreover, restrictive lung
less, our data demonstrate that the presence of clubbing bodes a disease was recognized in another 5% of our patients, and 20% of
poor prognosis. deaths were related to respiratory failure. In a series of 20 patients
with POEMS followed up during a 10-year period, 25% had
Minimal criteria for the diagnosis and evolution of disease
pulmonary hypertension.43
A table and comparisons of the largest series of patients with the Cardiomyopathy and congestive heart disease were observed in
syndrome are provided in “Results.” In Table 1 we list the features 7 of our patients. These conditions have been reported in 3
associated with POEMS and set forth a proposed model of the other cases.7,42,46
minimal criteria needed to establish the diagnosis. Relapse and Both arterial and venous thromboses have been described in
additional new features can occur even in patients who have patients with POEMS syndrome. In our series, there were 18BLOOD, 1 APRIL 2003 䡠 VOLUME 101, NUMBER 7 POEMS SYNDROME: A RETROSPECTIVE REVIEW 2503
patients with stroke, myocardial infarction, and Budd-Chiari syn- Screening for the syndrome
drome. Lesprit et al26 observed 4 of 20 patients to have arterial
occlusion. An additional 15 patients with gangrene, ischemia, Screening for POEMS syndrome with serum protein electrophore-
myocardial infarction, splenic infarcts, and strokes have been sis alone is inadequate. Immunofixation of serum and urine and
reported.47-60 Vasospastic angina,61,62 pulmonary embolism, and metastatic bone survey are essential for all patients with unex-
Budd-Chiari syndrome also have been described.63,64 plained peripheral neuropathy. If the index of suspicion is high
In 4 of our patients, renal failure developed as a preterminal enough, bone marrow aspirate and biopsy with immunostaining
event. The renal histologic characteristics of patients with POEMS may be required. The predominance of monoclonal cannot be
have been described.29,36,48,65-76 Almost one half of these patients overemphasized. Skin, viscera, lymph nodes, and optic fundi
had coexistent Castleman disease. Light-chain deposition is not should be examined carefully. If the diagnosis is strongly sus-
observed. Instead, membranoproliferative features and evidence of pected, a thorough endocrine evaluation should be performed. If
endothelial injury are characteristic.36,48,66,71-73 the patient has respiratory symptoms, pulmonary function testing
and echocardiography should be performed.
Treatment strategies
Final comments
Because the pathogenesis of this multisystem disease is unclear,
treatment is not standardized. The light chain has been implicated We propose that the diagnosis of POEMS syndrome be predi-
because less than 5% of patients with POEMS syndrome have cated on the presence of major and minor criteria. Two major
monoclonal .5,8,9,34,78,104,124,127,128 The hypothesis implicating vas- criteria and at least one minor criterion should be satisfied to
cular endothelial growth factor25,28,30,37,65,99,126,129-131 eventually differentiate this syndrome from neuropathy associated with
may be validated, providing a uniform target for therapy. To avoid monoclonal gammopathy of undetermined significance, my-
the risk of systemic alkylator exposure, most would agree that for
eloma, and Waldenström disease. Primary systemic amyloidosis
an isolated plasmacytoma, radiation is the preferred treat-
also should be excluded. The major criteria include a polyneu-
ment.3,11,79,120,132 Systemic and skin symptoms tend to respond
ropathy and a clonal plasmaproliferative disorder (almost al-
sooner than do symptoms of neuropathy, with the former beginning
ways ). The minor criteria include osteosclerotic bone lesions;
to respond within 1 month and the latter within 3 to 6 months.
Besides radiation, many strategies have been used, including Castleman disease; papilledema; organomegaly, including lymph-
plasmapheresis, intravenous immunoglobulin, interferon alfa, cor- adenopathy; edema, pleural effusion, or ascites; endocrinopa-
ticosteroids, alkylators, azathioprine, autologous stem cell transplan- thy; and skin changes.
tation, tamoxifen, and transretinoic acid.3,7,8,11,20,21,48,63,71,79,96,97,100, Survival for patients with POEMS syndrome is better than
105-107,118,120,122,125,127,130,132-144 On the basis of our experience and previously reported, with median survival of 165 months, regard-
reports in the literature,105,125,134 neither plasmapheresis nor intrave- less of how many syndrome features, bone lesions, or plasma cells
nous immunoglobulin is effective treatment. Alkylators with or are present at diagnosis. Patients do not have the usual complica-
without corticosteroids are effective in some patients.7,100,105 High- tions of classic multiple myeloma. Radiation and chemotherapy are
dose chemotherapy with autologous stem cell support may be the most useful therapies. Ultimately, manipulation of the cytokine
considered.143-146 milieu may be the treatment of choice.
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